Evaluation of drug-drug interactions in drug metabolism: Differences and harmonization in guidance/guidelines.

The U.S. Drugs and Food Administration (FDA) and the Ministry of Health, Labor and Welfare of Japan (MHLW) issued the drastically revised draft guidance and final guideline on drug-drug interactions (DDI) in 2017 and 2018, respectively. One of the most drastic changes for the evaluation of inhibition potential of drug metabolizing enzymes in the liver using a basic model in these guidance and guideline are represented by the concept to use the unbound maximum concentration in the systemic circulation as the investigational drug concentration instead of the total maximum concentration and the corresponding cutoff values are applied in harmonization with the current DDI guideline of Europe. In this review, the current DDI guidance and guidelines of the three regions are compared and the points which are in common are described. In addition, several issues to be considered and/or clarified such as a criterion for the metabolites to be evaluated as perpetrator drugs, details of in vitro study design etc. are also briefly summarized. Based on further accumulation of data and information, and their continuous international scientific discussion, these issues are expected to be solved to make the current DDI guidance and guidelines be much more harmonized and practically available standards.